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At least 811 records · Page 45Linked to original sources
PubMed2003

Na+ channel mutation leading to loss of function and non-progressive cardiac conduction defects.

BACKGROUND: We previously described a Dutch family in which congenital cardiac conduction disorder has clinically been identified. The ECG of the index patient showed a first-degree AV block associated with extensive ventricular conduction delay. Sequencing of the SCN5A locus coding for the human cardiac Na+ channel revealed a single nucleotide deletion at position 5280, resulting in a frame-shift in the sequence coding for the pore region of domain IV and a premature stop codon at the C-terminus. METHODS AND RESULTS: Wild type and mutant Na+ channel proteins were expressed in Xenopus laevis oocytes and in mammalian cells. Voltage clamp experiments demonstrated the presence of fast activating and inactivating inward currents in cells expressing the wild type channel alone or in combination with the beta1 subinut (SCN1B). In contrast, cells expressing the mutant channels did not show any activation of inward current with or without the beta1 subunit. Culturing transfected cells at 25 degrees C did not restore the Na+ channel activity of the mutant protein. Transient expression of WT and mutant Na+ channels in the form of GFP fusion proteins in COS-7 cells indicated protein expression in the cytosol. But in contrast to WT channels were not associated with the plasma membrane. CONCLUSIONS: The SCN5A/5280delG mutation results in the translation into non-function channel proteins that do not reach the plasma membrane. This could explain the cardiac conduction defects in patients carrying the mutation.

Animals↗
PubMed1998

Proliferative activity and loss of function of tumour suppressor genes as 'biomarkers' in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma.

Oral cancer is a disease of the elderly and is closely connected with cigarette smoking and alcohol consumption. Since the successful introduction of multidisciplinary treatment, the survival rate has not changed. Because of the high mortality and potentially disfiguring treatment, today's efforts are aimed at eliminating risk factors, chemoprophylaxis, improvement in diagnostic procedures, and understanding of the genetic mechanisms of oral carcinogenesis. Immunohistochemical and molecular biology analysis of biopsy tissue and cell lines of preneoplastic and neoplastic lesions that originate from the oral mucosa have shown that alterations in tumour suppressor genes such as p53 and Rb gene may have an important role in oral carcinogenesis and may be potentially useful prognostic 'biomarkers' in oral carcinogenesis. Statistical analysis of immunohistochemical data from 216 patients did not identify significant or consistent differences of p53, MDM2, or RB expression with respect to stage of disease, malignant transformation, metastatic node involvement, recurrence, or survival. Nevertheless, p53 overexpression seems to correlate strongly with histological progression of the disease, which confirms the importance of p53 alterations in oral carcinogenesis. Overexpression of p53 is usually found in the less differentiated proliferating cells in benign and malignant oral lesions. Assessment of the proliferating activity is possible by immunohistochemical staining with monoclonal antibodies against proliferating nuclear antigen and Ki-67. Statistical analysis shows that overexpression of p53 combined with high proliferative activity predicts a less favourable course of disease in oral squamous cell carcinoma.

Aged↗
PubMed2003

Close relationship between motor impairments and loss of functional motoneurons in a Charcot-Marie-Tooth type 1A model.

Charcot-Marie-Tooth disease type 1A is the most frequent hereditary neuropathy affecting the peripheral nervous system. A partial duplication of chromosome 17 (17p11.2) involving the PMP22 gene is responsible for dysmyelination-demyelination processes leading to motor and sensory impairments. Murine models of this disease are now widely used to investigate the mechanisms occurring at the behavioural and physiological levels. In this study, adult transgenic mice (6 months old) having integrated 7 copies of the human PMP22 gene were used to compare the motor performance, evaluated by using a complex locomotor test (the rotarod test), with both the number of functional motoneurons innervating the soleus muscle and the level of myelination in the sciatic nerve. Two levels of motor deficits were detected and led us to divide the population into two subgroups. In both impaired groups, the level of motor deficit was strongly correlated with the number of functional motoneurons evaluated by retrograde labeling from the muscle, but not with the number of myelinated fibers or the thickness of the myelin sheath (g-ratio). It therefore appears that the number of motor units may be a key element in motor impairments observed in Charcot-Marie-Tooth disease type 1A disease. These findings may have implications for therapeutic procedures, which should focus on the survival of the motoneuronal pool and/or the maintenance of functional neuro-muscular connexions to reduce motor impairments in humans.

Animals↗
PubMed1999

Pain and loss of function in head and neck cancer survivors.

Head and neck cancers are relatively uncommon malignancies and the characteristics of pain and functional impairments in survivors are not well studied. To characterize the incidence, location, severity, types and causes of pain; associated functional impairments, and pain management methods, the medical charts of 40 consecutive outpatients with biopsy-proven head and neck cancers were reviewed. Pain was severe in 52% (N = 21), and was located near sites of tumor origin. Pain was caused by tumor recurrence in 35% (N = 14), treatment sequelae in 30% (N = 12), multiple etiologies in 25% (N = 10), and unrelated causes in 10% (N = 4). Pains were mixed nociceptive and neuropathic pain in 37.5% (N = 15), nociceptive pain in 32.5% (N = 13), myofascial in 13.0% (N = 6), neuropathic in 7.5% (N = 3); and other mixed types in 7.5% (N = 3). Despite the high prevalence of dysphagia (82%), 60% used orally administered opioid-nonopioid analgesics. Physical disfigurement (87.5%; N = 35), dysphagia (62.5%, N = 25), and jaw dysfunction (40.0%; N = 16) were the most frequent physical impairments. Multiple regression analysis showed that the presence of skull base or mandibular bone involvement had significant influence on the severity of pain (P = 0.03, adjusted R2 0.25) We conclude that pain in head and neck cancer can be chronic, severe, and persistent despite completion of oncologic treatment.

Adult↗
PubMed1998

In vivo evaluation of in vitro hypothesis using "gain or loss" of function: functional analysis of renin-angiotensin system.

Characterization of the role of components of the renin angiotensin system (RAS) in vivo is limited by the difficulty in manipulating these individual components, as well as by methodologic limitations in studying the function of a local RAS in the absence of any contribution by the circulating RAS. In vivo gene transfer technology provides us with the opportunity to study the physiologic responses to in vivo manipulation of the individual components related to hypertension (ie, by overexpression or inhibition) without changes in the circulating system. Using this technology, the importance of each component of RAS in blood pressure regulation has recently been shown. Such an approach may increase our understanding of the biology and pathobiology of the autocrine-paracrine system in hypertension. This review discusses the potential utility of in vivo gene transfer methods.

Animals↗
PubMed1997

Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia.

Embryonic retinal ganglion cell (RGC) axons must extend toward and grow through the optic disc to exit the eye into the optic nerve. In the embryonic mouse eye, we found that immunoreactivity for the axon guidance molecule netrin-1 was specifically on neuroepithelial cells at the disk surrounding exiting RGC axons, and RGC axons express the netrin receptor, DCC (deleted in colorectal cancer). In vitro, anti-DCC antibodies reduced RGC neurite outgrowth responses to netrin-1. In netrin-1- and DCC-deficient embryos, RGC axon pathfinding to the disc was unaffected; however, axons failed to exit into the optic nerve, resulting in optic nerve hypoplasia. Thus, netrin-1 through DCC appears to guide RGC axons locally at the optic disc rather than at long range, apparently reflecting the localization of netrin-1 protein to the vicinity of netrin-1-producing cells at the optic disc.

Animals↗
PubMedDate not supplied

Muscle strength as a predictor of loss of functional status in hospitalized patients.

OBJECTIVE: The incidence of protein-calorie malnutrition in hospitalized adult patients can reach 30% to 50% and adversely affect clinical outcome. We evaluated the efficacy of muscle strength to predict functional derangement and detect early changes in nutrition status in hospitalized patients. METHODS: Patients hospitalized at medical and surgical wards from two different hospitals in Santiago, Chile, were studied during their hospital stay. Subjective Global Assessment of nutrition status and laboratory parameters were measured on admission. Anthropometric measures, handgrip dynamometry, and maximal inspiratory and expiratory pressures were measured on admission and discharge. The Karnofsky index was used to assess functional status. Twice weekly, caloric balance was calculated with indirect calorimetry and assessment of dietary intake. RESULTS: From the initial selection of patients (n = 70), 50 patients (26 men and 24 women) completed the study. Median hospital stay was 10 d. Subjective Global Assessment was associated with anthropometric data, handgrip dynamometry, and serum levels of total proteins. Patients in whom functional status declined during hospital stay, on admission had lower left handgrip strength, a worse Subjective Global Assessment classification, were older, and had lower fat mass. No association between caloric balance during hospital stay and changes in muscle strength was observed. CONCLUSIONS: Subjective Global Assessment, handgrip strength, and fat mass were good predictors for the decline in functional status during hospital stay. No association between caloric balance and changes in muscle strength was observed.

Adult↗
PubMed2026

Toward Class Imbalance and Uncertainty in Powder XRD Analysis: A Dual-Channel Fusion Network for Space Group Classification.

Accurate identification of space groups from powder X-ray diffraction (pXRD) is essential for understanding crystal structures and accelerating materials discovery. However, this task remains highly challenging due to inherent peak overlap, experimental noise, and the complexity of the 230-class classification problem. To address the critical issues of class imbalance and data scarcity, we first design a general physics-informed data augmentation pipeline. We then propose a dual-channel fusion uncertainty-aware network (DFUN) for automated space group classification. The DFUN architecture integrates two complementary feature representations: convolutional features extracted directly from raw diffraction profiles and domain-specific peak descriptors. These distinct representations are adaptively fused through a gating mechanism. Furthermore, to mitigate the inherent long-tailed distribution of crystallographic data, we employ a hybrid loss function that combines Focal Loss with Label Smoothing. Finally, we incorporate Monte Carlo Dropout to provide predictive uncertainty estimation, thereby enabling not only accurate classification but also a crucial assessment of the model's reliability. Evaluated on large-scale simulated data and two public data sets (opXRD and RRUFF), DFUN outperforms the evaluated baseline methods across the reported metrics. The framework also provides uncertainty-aware predictions, establishing DFUN as a robust and interpretable solution for high-throughput automated crystallographic analysis from powder diffraction.

Uncertainty↗
PubMed1992

Mutational analysis of carbamyl phosphate synthetase. Substitution of Glu841 leads to loss of functional coupling between the two catalytic domains of the synthetase subunit.

The synthetase subunit of Escherichia coli carbamyl phosphate synthetase has two catalytic nucleotide-binding domains, one involved in the activation of HCO3- and the second in phosphorylation of carbamate. Here we show that a Glu841----Lys841 substitution in a putative ATP-binding domain located in the carboxyl half of the synthetase abolishes overall synthesis of carbamyl phosphate with either glutamine or NH3 as the nitrogen source. Measurements of partial activities indicate that while HCO3(-)-dependent ATP hydrolysis at saturating concentrations of substrate proceeds at higher than normal rates, ATP synthesis from ADP and carbamyl phosphate is nearly completely suppressed by the mutation. These results indicate Glu841 to be an essential residue for the phosphorylation of carbamate in the terminal step of the catalytic mechanism. The Lys841 substitution also affects the kinetic properties of the HCO3- activation site. Both kcat and Km for ATP increase 10-fold, while Km for HCO3- is increased 100-fold. Significantly, NH3 decreases rather than stimulates Pi release from ATP in the HCO3(-)-dependent ATPase reaction. The increase in kcat of the HCO3(-)-dependent ATPase reaction, and an impaired ability of the Lys841 enzyme to catalyze the reaction of NH3 with carboxy phosphate, strongly argues for interactions between the two catalytic ATP sites that couple the formation of enzyme-bound carbamate with its phosphorylation.

Adenosine Diphosphate↗
PubMed2001

Mutations of the asparagine117 residue of a receptor activity-modifying protein 1-dependent human calcitonin gene-related peptide receptor result in selective loss of function.

The initially orphan human calcitonin (CT) receptor-like receptor (hCRLR) interacts with novel accessory receptor activity-modifying protein 1 (RAMP1) to reveal a functional CT gene-related peptide (CGRP) receptor. In mammalian cells, RAMP1 is required for mature N-glycosylation of the hCRLR predicted to occur at Asn(60), Asn(112), and/or Asn(117) in the amino-terminal extracellular domain. Here we have shown that the substitution of Asn(117) with Ala, Gln, Thr, or Pro abolished CGRP-evoked cAMP formation which was left unchanged when the Asn(117) was replaced with Asp. Moreover, the hCRLR and the Asn(117) mutants exhibited comparable N-glycosylation and cell surface expression, and the association with RAMP1 was only slightly impaired. In contrast, the hCRLR Asn(60,112) to Thr double mutant exhibited defective RAMP1-dependent N-glycosylation, and impaired cell surface expression and CGRP receptor function. Unlike Asn(60) and Asn(112), Asn(117) is normally not N-glycosylated, but essential for CGRP binding to the hCRLR-RAMP1 complex.

Amino Acid Substitution↗
PubMed1993

Generating loss-of-function phenotypes of the fushi tarazu gene with a targeted ribozyme in Drosophila.

The ability to isolate gene sequences and analyse their expression patterns has generated demand for mutations created to assess their biological functions. In Drosophila melanogaster this can be achieved by traditional mutagenesis, but this is time-consuming, labour-intensive and not always successful. Moreover, the functions of genes that are expressed several times during development are often obscured in the later stages because of disruptions caused by the absence of early gene function. Here we propose a new strategy to create conditional knock-out mutations using a targeted heat-inducible ribozyme. Ribozymes are catalytic RNA molecules that specifically cleave RNAs and are potentially useful for studying gene function during animal development because the expression of critical regulatory genes is usually low and their function is often dosage-dependent. The ribozyme can be delivered to a specific region or at a particular developmental stage using a region-specific or inducible promoter. The Drosophila fushi tarazu (ftz) gene is a good candidate for testing this approach. We generated transgenic flies carrying a ribozyme against the ftz gene. The two developmental phases of ftz function can be distinguished by timed induction of the ribozyme. Activation of the ribozyme in the blastoderm disrupts the ftz seven-stripe pattern and produces ftz-like pair-rule defects in larvae. The involvement of ftz in neurogenesis was verified by activation of the ribozyme during the early phase of formation of the central nervous system.

Animals↗
PubMed2004

Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase.

We identified an autosomal recessive infantile-onset symptomatic epilepsy syndrome associated with developmental stagnation and blindness. Assuming a founder effect in a large Old Order Amish pedigree, we carried out a genome-wide screen for linkage and identified a single region of homozygosity on chromosome 2p12-p11.2 spanning 5.1 cM (maximum lod score of 6.84). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase is a member of the sialyltransferase family and catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lack GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this is the first report, to our knowledge, of a disruption of ganglioside biosynthesis associated with human disease.

Blindness↗
PubMed2005

Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts.

Dysfunction of receptors for IgG (FcgammaRs) has been thought to be involved in the pathogenesis of systemic lupus erythematosus (SLE). We show that a recently described SLE-associated polymorphism of FcgammaRIIb (FcgammaRIIbT(232)), encoding a single transmembrane amino acid substitution, is functionally impaired. FcgammaRIIbT(232) is unable to inhibit activatory receptors because it is excluded from sphingolipid rafts, resulting in the unopposed proinflammatory signaling thought to promote SLE.

Amino Acid Substitution↗
PubMed1996

Loss of functional KATP channels in pancreatic beta-cells causes persistent hyperinsulinemic hypoglycemia of infancy.

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder of childhood associated with inappropriate hypersecretion of insulin by the pancreas. The pathogenesis of the condition has hitherto remained controversial. We show here that insulin-secreting cells from a homogeneous group of five infants with PHHI lack ATP-sensitive K+ channel (KATP) activity. As a consequence, PHHI beta-cells are spontaneously electrically active with high basal cytosolic Ca2+ concentrations due to Ca2+ influx. Our findings define the pathogenesis of this disease as a novel K+ channel disorder.

ATP-Binding Cassette Transporters↗
PubMed2005

The RUNX genes: gain or loss of function in cancer.

The RUNX genes have come to prominence recently because of their roles as essential regulators of cell fate in development and their paradoxical effects in cancer, in which they can function either as tumour-suppressor genes or dominant oncogenes according to context. How can this family of transcription factors have such an ambiguous role in cancer? How and where do these genes impinge on the pathways that regulate growth control and differentiation? And what is the evidence for a wider role for the RUNX genes in non-haematopoietic cancers?

Animals↗